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Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1517-1521

Somatic mitochondrial DNA D-loop mutations in meningioma discovered: A preliminary data


1 Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
2 Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia; Center for Neuroscience Services and Research, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

Date of Submission12-Oct-2016
Date of Decision14-Aug-2017
Date of Acceptance24-Feb-2018
Date of Web Publication26-Oct-2018

Correspondence Address:
Abdul Aziz Mohamed Yusoff
Department of Neurosciences, School of Medical, Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1132_16

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 > Abstract 


Background and Objective: Meningiomas are among the most common intracranial tumors of the central nervous system. It is widely accepted that the initiation and progression of meningiomas involve the accumulation of nucleus genetic alterations, but little is known about the implication of mitochondrial genomic alterations during development of these tumors. The human mitochondrial DNA (mtDNA) contains a short hypervariable, noncoding displacement loop control region known as the D-Loop. Alterations in the mtDNA D-loop have been reported to occur in most types of human cancers. The purpose of this study was to assess the mtDNA D-loop mutations in Malaysian meningioma patients.
Materials and Methods: Genomic DNA was extracted from 21 fresh-frozen tumor tissues and blood samples of the same meningioma patients. The entire mtDNA D-loop region (positions 16024-576) was polymerase chain reaction amplified using designed primers, and then amplification products were purified before the direct DNA sequencing proceeds.
Results: Overall, 10 (47.6%) patients were detected to harbor a total of 27 somatic mtDNA D-loop mutations. Most of these mtDNA mutations were identified in the hypervariable segment II (40.7%), with 33.3% being located mainly in the conserved sequence block II of the D310 sequence. Furthermore, 58 different germline variations were observed at 21 nucleotide positions.
Conclusion: Our results suggest that mtDNA alterations in the D-loop region may be an important and early event in developing meningioma. Further studies are needed, including validation in a larger patient cohort, to verify the clinicopathological outcomes of mtDNA mutation biomarkers in meningiomas.

Keywords: D-loop, meningioma, mitochondrial DNA, somatic mutations


How to cite this article:
Mohamed Yusoff AA, Mohd Khair SZ, Wan Abdullah WS, Abd Radzak SM, Abdullah JM. Somatic mitochondrial DNA D-loop mutations in meningioma discovered: A preliminary data. J Can Res Ther 2020;16:1517-21

How to cite this URL:
Mohamed Yusoff AA, Mohd Khair SZ, Wan Abdullah WS, Abd Radzak SM, Abdullah JM. Somatic mitochondrial DNA D-loop mutations in meningioma discovered: A preliminary data. J Can Res Ther [serial online] 2020 [cited 2021 Nov 27];16:1517-21. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1517/244199




 > Introduction Top


Meningiomas, originate from arachnoid cap cells in the meninges covering of the brain, are one of the most frequent intracranial tumors. They made up 20%–36% of all primary tumors with an average annual incidence rate of about 1.8–13 per 100,000 population.[1],[2] In Malaysia, meningiomas account for approximately 32.3% of all primary brain tumors.[3] The majority of meningiomas are benign, slow-growing tumors. The World Health Organization (WHO) classification system uses the terms benign (WHO Grade I), atypical (WHO Grade II), and anaplastic (malignant; WHO Grade III) to describe the overall grades of meningiomas.[2]

The progression of meningiomas involves multiple genetic abnormalities which include both chromosomal aberrations and some gene alterations. Among these genetic abnormalities, loss of chromosome 22, including the neurofibromatosis Type 2 gene at 22q12.2, has been often detected in early meningioma formation.[4],[5],[6] Meanwhile, several additional genes have also been implicated in meningiomas progression, such as mutation of the PTEN,[7] CDKN2A,[8] CDKN2B,[8] p14ARF,[8] and SMARCB1 gene.[9] Even though alterations of genes encoded by DNA in nuclear chromosomes are believed and well recognized to be involved in the formation and progression of meningiomas, the connection of extrachromosomal mitochondrial DNA (mtDNA) in these tumors remains unclear.

Mitochondria have long been discovered as the first “nonnuclear” cellular organelles that contain their own extrachromosomal, separate from the vast majority of cellular DNA found in the nucleus. They are recognized for their essential role in generating energy for the cell. Recently, numerous cancer researches have been aggressively conducted with focusing on the role of mitochondrial defect in carcinogenesis. A large number of mitochondrial defects associated with cancer have been identified; the most common ones are alterations in the oxidative phosphorylation complexes and mtDNA mutations. Somatic mutations of mtDNA have been reported in various types of human cancer including colorectal cancer,[10],[11] ovarian cancer,[12],[13] prostate cancer,[14],[15] breast cancer,[16],[17] hepatocellular carcinoma,[18] gastric cancer,[19] and lung cancer.[20] Most of the mtDNA mutations are discovered in the D-loop region.

To date, the influence of mtDNA mutations has not been tested in meningioma patients particularly in Malaysian patient populations. Only one study by Vega et al.[21] had investigated the occurrence of mtDNA mutations in the central nervous system (CNS) tumor with the small number of meningioma patients involved. Since the study of mtDNA alterations associated with meningiomas has received considerably less attention, the lack of published data or reports on this led us to analyze the hotspot region of mtDNA which is the D-loop region in patients with meningiomas. The main intention of this study was to screen D-loop region of mtDNA for somatic mutation in both tumor tissue and blood samples from 21 Malaysian patients with meningiomas.


 > Materials and Methods Top


Patient selection

This study was conducted in Neurosciences Laboratory, Department of Neurosciences, Universiti Sains Malaysia. A total of 21 adult meningioma patients (12 males and 9 females; with a median age of 47 years, range 23–74 years) were identified, all with WHO grade I. The histological subtypes of the tumors were as follows: 12 meningothelial, 5 transitional, and 4 fibroblastic. Before beginning the study, informed consent was given by all patients and the study was approved by the university ethics committee. Paired tumor tissue and blood samples from each meningioma patients were obtained and used for DNA isolation.

DNA isolation

Both blood and tumor DNA samples were isolated using the QIAamp DNA mini kit (Qiagen, Germany), according to manufacturer's protocol. The concentration and quality of extracted DNA were measured using the NanoDrop ND1000 spectrophotometer (Agilent Technologies, USA) and 1% agarose gel electrophoresis.

Polymerase chain reaction amplification and DNA sequencing analysis of the mtDNA D-loop

Polymerase chain reaction (PCR) amplification was performed to amplify three overlapping PCR fragments that spanning the entire mtDNA D-loop region within nucleotide position 16024-576. The following three pairs of primers were designed using Primer-BLAST software (http://www.ncbi.nlm.nih.gov/tools/primer-blast/): MD-loop1_F: 5'-CCTATGTCGCAGTATCTGTC-3', MD-loop1_R: 5'-TGCTTTGAGGAGGTAAGCTA-3' spanning np 113-603 (491 bp); MD-loop2_F: 5'-GTCTTGTAAACCGGAGATGA-3', MD-loop2_R: 5'-GAGCGAGGAGAGTAGCAC-3' spanning np 15,915-16,453 (539 bp); MD-loop3_F: 5'-TACAGTCAAATCCCTTCTCG-3', MD-loop3_R: 5'-AATAGGATGAGGCAGGAATC-3' spanning np 16,342-155 (383 bp). PCR cycles consist of initial denaturation of 98°C for 1 min, followed by 35 cycles of 98°C for 20 s, 56°C for 20 s, and 72°C for 20 s with a final extension step at 72°C for 5 min. The amplified PCR products were visualized using 2% agarose gel electrophoresis and subjected to DNA sequencing analysis with the forward and/or reverse primers. Before DNA sequencing analysis, PCR products were purified with the use of QIAquick PCR Purification kit (QIAGEN, Germany) and labeled with BigDye Terminator cycle sequencing kit (Applied Biosystems, USA) according to the manufacturer's instructions. DNA sequencing analysis was performed on the ABI Prism 3700 DNA Automated Analyzer (Applied Biosystems, USA), and the sequence results were compared with the published revised Cambridge Reference Sequence of the human mtDNA (NC_012920) in the MITOMAP database (www.mitomap.org).


 > Results Top


Matched tumor and blood samples from 21 patients with WHO Grade I meningioma were investigated for the mtDNA D-loop mutations. All of the samples were obtained from Malaysian patients. Overall, 10 (47.6%) of 21 meningiomas were discovered to harbor a total of 27 somatic mutations in 14 nucleotide positions of D-loop region [Table 1]. According to histopathological subtypes, the D-loop mutations were more detected in meningothelial tumor patients (n = 6/10, 60%), followed by transitional tumor (n = 3/10, 30%) and fibroblastic tumor (n = 1/10, 10%).
Table 1: Somatic mitochondrial DNA D-loop mutation in meningioma

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All of the somatic mutations identified here were homoplasmic. Majority of these somatic mutations were located in hypervariable segment II (HVII) (11/27, 40.7%) and only 1 mutation occurred in HVI and HVIII. Four (14.8%) of the mutations were specifically located in the mitochondrial transcription factor A (TFAM) binding site and three mutations were unknown. In addition, 9 (33.3%) of the mutations were positioned in the D310 mononucleotide repeat with the insertion of one cytosine. As shown in [Figure 1], the representative DNA sequence chromatograms showed the D-loop somatic mutation at nucleotide 146 with the T-to-C transition.
Figure 1: Electropherogram of the mitochondrial DNA D-loop from the meningioma tissue patient and blood sample showing a homoplasmic mutation. An arrow indicates the T-to-C transition at nucleotide position 146

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Numerous germline variations were identified after analyzing sequences from both blood and tumor tissue of the same patient. Overall, 58 germline variations were found at 21 nucleotide positions [Table 2]. Most of variations were occurred in HVI (41/58, 70.7%) and only 15 variations were located in HV2, accounting for 25.9%. Moreover, the 263A>G nucleotide (13/58, 22.4%) showed higher variation frequency than other nucleotide positions.
Table 2: Mitochondrial DNA D-loop germline variations in meningioma

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 > Discussion Top


The somatic mutation of the mtDNA is relatively common in various human cancers and usually affects “hot-spot” noncoding region of D-loop.[22],[23],[24],[25],[26] In the present study, we focused on 21 meningioma WHO grade I patients (due to lack of high grade meningioma patients) who were screened for mutations of the entire mtDNA D-loop region in the Hospital Universiti Sains Malaysia. Our results revealed that mtDNA mutations were detected in 47.6% of meningiomas. To our knowledge, there is only one previous published study in which the meningioma cases were found to have mtDNA mutations.[21] Vega et al.[21] reported that 45.5% (5/11) of meningioma tissue samples showed mtDNA changes in the D-loop sequences as compared to blood samples. Our mutation rate is quite close to those of Vega et al.'s findings.

The reported incidence of mtDNA mutations in CNS tumor is also dictated by their different types.[21],[27],[28],[29] Compared with the results obtained by other types of CNS tumor, our rate of mtDNA mutations is quite high compared with those previously published: A study conducted by Kirches et al.[27] had found 41% frequency of the mtDNA mutations in glioblastoma patients.[27] In 2004, Kurtz et al.[28] revealed that mtDNA mutation rate was 40% in the neurofibromatosis type 1-associated tumors.[28] In addition, Lueth et al.[29] reported an amount of 40% frequency of the mtDNA mutations in medulloblastoma patients.[29] However, our rate was considered lower than those reported in pilocytic astrocytoma with a mutation frequency of 84%.[30] The discrepancy in the reported frequency of mtDNA mutations may be due to many different factors, including sample size of the study, different types of CNS tumors, and the ethnic/genetic backgrounds difference among studied populations.

All nucleotide alterations in our study have been previously recognized in MITOMAP database, meaning that no novel mutations of mtDNA were found in our study patients. Mutations at nucleotides 73, 146, 152, 195, and 311, which have been described before in meningioma patients by Vega et al.,[21] were also discovered to harbor mutations in our meningioma samples. Furthermore, mutations at these nucleotides have also been reported in breast cancer,[16],[23],[31] laryngeal cancer,[32] leukemia,[33] oral cancer,[25] and other brain tumors such as high-grade gliomas[21],[27] and neurofibromas.[28]

Our study demonstrates that the HVII segment is a frequently mutated area, in which 9 of 11 mutations occurred mainly in the conserved sequence block II of the D310 sequence (a polycytosine mononucleotide repeat tract located between 303 and 315 nucleotides). Alterations in the D310 sequence, whether base deletions or insertions, are the most common mtDNA changes found in diverse human cancers, including in brain tumors.[22],[29],[30],[34],[35] The D310 sequence is an important element for mtDNA replication because it contains the H-strand replication origin. Thus, mutations in the D310 sequence may influence the rate of mtDNA replication by impairing the binding of mtDNA polymerase γ and other trans-acting factors.[36] Decreased mtDNA copy number has been reported in 61% of hepatocellular carcinoma with mtDNA D-loop somatic mutations.[37] It has been postulated that reduction of mtDNA content in cancer may consequently give rise to mitochondrial genomic instability, leading to alterations in energy metabolism and promoting tumor progression.[38]

Any sequence variation identified in both tumor tissue and peripheral blood of tested patients was classified as germline variations. In our study, we found 58 germline nucleotide variations which can also be considered as polymorphisms. The 263A>G germline variations seem to account for the majority of polymorphisms in our meningioma patients. It has been reported that the Tunisian women associated with 263A>G germline polymorphisms showed a weak protective effect against breast cancer risk.[39] A high frequency of 263A>G polymorphism has been also demonstrated by Lueth et al.[29] in medulloblastoma patients. However, there was no mention about a link between this polymorphism and the tumors. Up to now, it is still unknown whether all polymorphisms that found in our study play a role in the etiology of brain tumors.

In this study, we did not find any significant difference between the D-loop mutation group and nonmutation group in gender and age during diagnosis. Due to the incomplete information available of the patients and pathological features of the meningioma, we could not address a complete relationship between the mtDNA D-loop mutation status and other pathological phenotypes or clinical data. Our study was limited to grade I meningiomas and by screening noncoding D-loop region mutations only. Therefore, further study with larger population is needed, including patients with high-grade (WHO II and III) meningiomas, to clarify whether mtDNA mutation status is correlated to clinical outcome in meningioma. Extensive investigations are also required not only in the mtDNA non-coding region but need to be expanded on the entire coding region or the whole of 37 genes of mitochondrial genome if necessary. However, we believe that these mtDNA D-loop mutations are capable in initiating and promoting tumorigenesis of the brain tumors, especially in meningiomas.


 > conclusion Top


In summary, this is the second study to report the mutations of the mtDNA D-loop in meningioma cases and the first study involved Malaysian patients. Considering both previous data and our findings, we believe that mtDNA alterations appear to play an important role subsequent to nuclear DNA in various types of human tumors, including meningioma. Our initial local data in mtDNA mutations would facilitate in discovery of biomarker and development of effective diagnostics and therapeutic in brain tumors.

Acknowledgments

We would like to thank the patients who participated in this study. We also thank and acknowledge all of the researchers and clinicians who are not listed as authors but worked to make this study possible.

Financial support and sponsorship

This study was financially supported by Universiti Sains Malaysia short-term grant (304/PPSP/61310010) and Fundamental Research Grant Scheme (FRGS) (203/PPSP/6171161) from the Ministry of Higher Education of Malaysia.

Conflicts of interest

There are no conflicts of interest.



 
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